CircFOXK2 Functions as a Protein Encode and a microRNA Sponge to Promote Hepatocellular Carcinoma Progression and Lead a Poor Clinical Prognosis via Regulating the Warburg Effect

Background: The Warburg effect is essential for tumor progression, metastasis, and drug resistance, causing poor clinical outcomes in patients with hepatocellular carcinoma (HCC). Circular RNAs (circRNAs) have emerged as important regulators in HCC development and progression. However, limited circRNAs involved in the Warburg effect of HCC have been investigated. Herein, we aimed to explore the contribution of a novel circRNA that derived from the FOXK2 gene locus, circFOXK2, to the reprogramming of glucose metabolism of HCC. Methods Firstly, we constructed divergent primers to identify 14 circRNAs originated from FOXK2 gene followed by investigating their differential expression between HCC specimens and the adjacent normal tissues (ANTs), and circFOXK2 (has_circ_0000817) was screened for further research. Next, the clinical significance of circFOXK2 for the patients with HCC was evaluated, coupled with evaluating its onco-promoting activity and the affection to the Warburg effect in both HCC cell lines and animal xenograft. Finally, the molecular mechanisms underlying circFOXK2 regulating the Warburg effect of HCC were explored. Results We showed that circFOXK2 was aberrantly upregulation in HCC tissues, and its expression was positively correlated with poor clinical outcomes in patients receiving radical hepatectomy. And silenced circFOXK2 remarkably suppressed the progression of HCC both in vitro and in vivo. Mechanistically, we unveiled that circFOXK2 not only encoded a novel protein, FOXK2-142aa, to promote LDHA phosphorylation but also inactivated miR-484 and subsequently promoted Fis1 expression leading to mitochondrial fission, which activate the Warburg effect in HCC. Conclusions CircFOXK2, a prognostic biomarker of the disease, exerts critical roles in promoting the Warburg effect through its roles in protein encode and miRNA sponge so that leading tumor progression, indicating that circFOXK2 may serve as a potential therapeutic target for patients with HCC.